Novel tropolone derivatives



United States Patent 5 Claims ABSTRACT OF THE DISCLOSURE This disclosurerelates to substituted thienyl, furyl, nitrofuryl, pyridyl, naphthyl andindole derivatives of 6- hydroxy-7-oXo-1,3,5cycloheptatriene-l-carboxylic acids and salts thereof. The compounds ofthis disclosure have been found to possess anti-microbial activity.

This is a divisional application of US. application, Ser. No. 247,274,filed Dec. 26, 1962 now US. Patent No. 3,326,963.

This invention relates to new compounds and more particularly tocompounds of the general Formula I:

and acid-addition and quaternary ammonium salts thereof, wherein A islower alkylene; B is a basic nitrogen-containing radical of less than 12carbon atoms; and R is phenyl, an (X) -substituted phenyl, thienyl,furyl, nitrofuryl, pyridyl, naphthyl and indolyl, wherein X is hydrogen,halogen (e.g., chloro and bromo), trifluoromethyl, nitro, lower alkyl,lower alkoxy and lower alkenoyl (e.g., acetyl and propionyl), and n is1, 2 or 3.

Among the suitable radicals represented by the symbol B are: amino,(lower alkyl)amino; di(lower alkyl)amino; (hydroxy-lower alkyl)amino;di(hydroxy-lower alkyl) amino; (X -substituted phenyl(lower alkyl)amino;N- (lower alkyl)-N-[(XE-substituted phenyl(lower alkyl)]- amino;allylamino; diallylamino; and saturated 5 to 6- membered monocyclicheterocyclic radicals of less than twelve carbon atoms, as exemplifiedby piperidino; (lower alkyl)piperidino; di(lower alkyl)piperdino; (loweralkoxy)piperidino; 2, 3 or 4-piperidyl; 2, 3 or 4-(N-1oweralkyl-piperidyl); pyrrolidino; (lower alkyl)pyrrolidino; di(loweralkyl)pyrrolidino; (lower alkoxy)pyrrolidino; 2 or 3-pyrrolidyl; 2 or3-(N-lower alkyl-pyrrolidyl); morpholino; (lower alkyl)morpholino;di(lower alkyl)morpholino; (lower alkoxy)morpholino; thiamorpholino;(lower alkyl)thiamorpholino; di( lower alkyl)thiamorpholino; (loweralkoxy)thiamorpholino; piperazino; (lower alkyl)piperazino (e.g., N-methylpiperazino); di(lower alkyl)piperazino; (lower alkoxy)piperazino;(hydroxylower alkyl)piperazino (e.g. N -2-hydroxyethylpiper azino);(lower alkanoyloxy-lower alkyl)piperazino (e.g. N-2-acetoxyethylpiperazino) and (hydroxy-lower alkoxyloweralkyl)piperazino (e.g. N -2-hydroxyethoxyethyl) piperazino. The termslower alkyl and lower alkoxy as employed herein include both straightand branched chain radicals of less than eight carbon atoms.

The preferred compounds are those wherein B is is di (lower alkyl)aminoor N -met'hylpiperazino; A is ethylene or propylene; and R is phenyl,alkoxy phenyl, halo phenyl, Z-thienyl, Z-furyl S-nitrofuryl or4-pyridyl. Particularly preferred are those compounds wherein B isdi(lower alkyl)amino; A is ethylene or propylene and R is phenyl.

As to the salts, those coming within the purview of this inventioninclude acid-addition salts, particularly the nontoxic quaternaryammonium salts. Acids useful for preparing the acid-addition saltsinclude inter alia, inorganic acids, such as the hydrohalic acids (e.g.hydrochloric and hydrobromic acid), sulfuric acid, nitric acid, andphosphoric acid, and organic acids, such as oxalic, tartaric, malic,citric, acetic and succinic acid. Salts useful in preparing thequaternary ammonium salts include, inter alia, the lower alkyl halidesand sulfates (e.g. methyl chloride, methyl bromide and diethyl sulfate)and the monocyclic aryl(lower alkyl) halides and sulfates (e.g. benzylchloride).

The compounds of this invention are therapeutically active substanceswhich exhibit anti-microbial activity. The compounds of this inventionare useful as microbicides against such organisms as Staphylococcusaureas, K. pneumoniae, Trichophyton metagrophytes, BacillusCalmette-guerin.

The compounds of this invention may be administered orally, parenterallyor topically, the dosage being adjusted for the relative potency of theparticular compound, for example, the compounds of this invention may beadministered topically in the form of an ointment or cream, the vehiclefor which may be any pharmaceutically acceptable one known to the art tobe useful for such purposes. Oral administration may be accomplished inthe manner known to the art, for example, by tablet or capsule dosageforms, the dosage being adjusted for the particular compound employedand the requirements of the patient being treated.

The preferred and general method for preparing the compounds of thisinvention involves reacting a dicarboxylic acid of the general formulaOH O OH2COOH with an aromatic aldehyde of the formula R-CHO wherein R isas 'hereinbefore defined, to yield new styryl monocarboxylic acidintermediates of this invention of the general formula coon CH=CHR IIIwherein R is as hereinbefore defined.

Suitable aromatic aldehydes include benzaldehyde, chlorobenzaldehyde,trifiuoromethylbenzaldehyde, alkoxybenzaldehyde, such astrimethoxybenzaldehyde, indolealdehyde, furaldehyde, naphthaldehyde,pyridinealdehyde, thiophenealdehyde, nitrobenzaldehyde, toluylaldehyde,piperonyl aldehyde and S-nitrofuraldehyde.

The styryl mono-carboxylic acid of Formula III is then esterified byreaction with an appropriate basically substituted alkyl halide to yieldthe final products of this invention. Suitable basically substitutedalkyl halides include amino (lower alkyl) chlorides, such as2-aminoethyl chloride and 3-aminopropy1 chloride; (lower alkyl)amino(lower alkyl)chlorides such as methylaminomethyl chloride,Z-methylaminoethyl chloride, and 3-ethylaminopropyl chloride; di(loweralkyl)amino(lower alkyl) chlorides, such as Z-dimethylaminoethylchloride, 3-dimethylaminopropyl chloride, S-diethylaminopentyl chloride,and

2-dipropylaminohexyl chloride; (hydroxy-lower alkyl) amino(lower alkyl)chlorides, such as 2-(2-hydroxy ethyl)aminoethyl chloride;di(hydroxy-lower alkyl)amino (lower alkyl) chlorides such as3-(2-hydroxyethyl)aminopropyl chloride; phenyl(lower alkyl)amino(loweralkyl) chlorides, such as 2 benzylaminoethyl chloride, 3phenethylaminopropyl chloride, and 4-benzylaminobutyl chloride, and halotrifluoromethyl, nitro, lower alkyl and lower alkoxy substituted phenylderivatives thereof; N-(lower alkyl)phenyl(lower alkyl)amino chlorides,such as 2-(benzyl-methylamino)ethyl chloride, and halo, trifluoromethyl,nitro, lower alkyl and lower alkoxy substituted phenyl derivativesthereof; allyl amino(lower alkyl) chlorides, such as 2-allylaminoethylchloride; di(allyl)amino(lower alkyl) chlorides, such as3-diallylaminopropyl chloride; and saturated 5 to 6 membered monocyclicheterocyclic lower alkyl chlorides.

The following examples illustrate the invention, all temperatures beingin degrees centigrade.

EXAMPLE I 6 hydroxy 7 oxo 2 styryl 1,3,5 cycloheptatrienel-carboxylicacid, ester with 2-diethylaminoethano1 A. 6 hydroxy 7 oxo 2 -styryl1,3,5 cycloheptatriene-l-carboxylic acid (II).The reaction of 24.0 g. of3-carboxy-4-carboxymethyltropolone with 12 ml. of benzaldehyde iscarried out under the reaction conditions set forth in the Journal ofthe American Chemical Society, vol. 81, page 3443 (1959), to yield g. ofa crude yellow-brown product, M.P. about 163l66 C. This material is thentriturated with 50 ml. of hot acetonitrile, cooled and filtered to yield16.5 g. of 6-hydroxy-7-oxo-2- styryl-1,3,5-cycloheptatriene 1 carboxylicacid having a melting point of about l69171 C.

B. 6 hydroxy 7- oxo 2 -styryl 1,3,5 cycloheptatriene 1 carboxylic acid,ester with 2 diethylaminoethanol.-A mixture of 13.4 g. of6-hydroxy-7-oxo-2- styryl-1,3,5-cycloheptatriene-1-carboxylic acid in200 ml. of isopropyl alcohol is added to a solution of 1.15 g. of sodiumin 200 ml. of isopropyl alcohol. The sodium salt of the acidprecipitates from the mixture. After stirring for minutes, the mixtureis treated with 8.0 g. of 2-diethylaminoethyl chloride and heated toreflux temperature. 200 ml. of diglyme is added, the mixture continuedto reflux for four hours, and the solvent removed under reducedpressure. The residue is treated with 100 ml. of water, filtered anddried to yield 15.0 g. of 6-hydroxy-7- oxo-2-styryl-1,3,5cycloheptatriene 1 carboxylic acid, ester with 2-diethylaminoethanol,having a melting point of about 149-150 C. After crystallization from450 m1. of acetonitrile 11.2 g. of 6-hydroxy-7-oxo-2-styryl-1,3,5-cycloheptatriene-l-carboxylic acid, ester with 2 diethylaminoethanol,having a melting point of about 151-152 C., is obtained.

EXAMPLE 2 6 hydroxy 7 oxo 2 styryl 1,3,5-cycloheptatrienel-carboxylicacid, ester with Z-diethylaminoethanol, hydrochloride A suspension of1.0 g. of 6-hydroXy-7-oxo-2-styryl- 1,3,S-cycloheptatriene-l-carboxylicacid, ester with 2-diethylaminoethanol in 47 ml. of water is treatedwith 2.7

ml. of N-hydrochloric acid and the resulting solution is evaporatedunder reduced pressure to yield the hydrochloride salt of 6 hydroxy 7oxo 2-styryl-1,3,5-cycloheptatriene-l-carboxylic acid, ester withZ-diethylaminoethanol.

EXAMPLE 3 6 hydroxy 7 oxo 2 styryl 1,3,5 cycloheptatriene- 1 carboxylicacid, ester with 2 diethylaminoethanol, methochloride A suspension of5.0 g. of 6-hydroxy 7 oxo 2-styry1- 1,3,5 cycloheptatriene-l-carboxylicacid ester with 2-diethylaminoethanol in 150 ml. of acetonitrile istreated 4 with 15 g. of methyl chloride. After standing for one day atroom temperature, the solvent is removed under reduced pressure to givethe methochloride salt of 6-hydroxy-7-oxo-2-styryl-1,3,5cycloheptatriene-l-carboxylic acid, ester with 2-diethylaminoethanol.

EXAMPLE 4 6 hydroxy 7 0x0 2 styryl 1,3,5 cycloheptatrienel-carboxylicacid, ester with B-dimethylaminopropanol Following the procedure ofExample 1, part B, but substituting an equivalent amount of3-dimethylaminopropyl chloride for 2-diethylaminoethyl chloride yields 6-hydroxy-7-oxo-2-styryl-1,3,5 cycloheptatriene-l-carboxylic acid, esterwith 3-dimethylaminopropanol.

EXAMPLE 5 6 hydroxy 7 oxo 2 styryl 1,3,5 cycloheptatrienel-carboxylicacid, ester with N'-(3-hydroxypropyl)-N methylpiperazine Following theprocedure set forth in Example 1, part B, but substituting an equivalentamount of N-(3-chloropropyl) N methylpiperazine for 2 diethylaminoethylchloride yields6-hydroxy-7-oxo-2-styryl-1,3,5-cycloheptatriene-l-carboxylic acid, esterwith N-(3-hydroxypropyl)- N -methylpiperazine.

EXAMPLE 6 6 hydroxy 7 oxo 2 (4 chlorostyryl)1,3,5-cycloheptatriene-l-carboxylic acid, ester withZ-diethylaminoethanol A. 6 hydroxy 7 oxo 2 (4 chlorostyryl)-1,3,5-cycloheptatriene 1 carboxylic acid.Following the procedure set forth inExample 1, part A, but substituting an equivalent amount of4-chlorobenzaldehyde for benzaldehyde there is obtained 6 hydroxy 7oxo-2-(4 chlorostyryl)-1,3,5-cycloheptatriene-l-carboxylic acid.

B. 6 hydroxy 7 oxo 2 (4 chlorostyryl) 1,3,5-cycloheptatriene-l-carboxylic acid, ester with2-diethylaminoethanoL-Following the procedure set forth in Example l,part B, but substituting 6-hydroxy-7-oxo-2-(4-chlorostyryl)-1,3,5-cyclcheptatriene-l-carboxylic acid for 6hydroxy-7-oxo-2-styryl 1,3,5 cycloheptatriene-l-carboxylic acid, thereis obtained 6 hydroxy-7-oxo-2-(4- chlorostyryl)-1,3,5-cycloheptatriene 1carboxylic acid, ester with 2-diethylaminoethanol.

Similarly, when the 6 hydroxy 7 oxo-2-(4chlorostyryl)-1,3,S-cycloheptatriene 1 carboxylic acid is employed inthe procedures set forth in Examples 4 and- 5, there is obtained theB-dimethylaminopropanol and N'- (3-hydroxypropyl)-N -methylpiperazineesters of 6-hydroxy 7oxo-2-(4-chlorostyryl)-1,3,5-cycloheptatrienel-carboxylic acid,respectively.

EXAMPLE 7 6-hydroxy-7-oxo-2-(3trifiuoromethylstyryl)-1,3,5-cycloheptatriene-l-carboxylic acid, esterwith Z-diethylaminoethanol A. 6-hydroxy 7 oxo 2(3-trifiuoromethylstyryl)-1, 3,5-cycloheptatriene 1 carboxylicacid.Following the procedure set forth in Example 1, part A, butsubstituting an equivalent amount of 3-trifluoromethylbenzaldehyde forbenzaldehyde there is obtained 6-hydroxy-7-oxo-2-(3-trifluoromethylstyryl) 1,3,5 cycloheptatriene 1 carboxylic acid.

B. 6-hydroxy 7 ox-o 2 (3-trifluoromethylstyryl)-1, 3,5-cycloheptatriene1 carboxylic acid, ester with 2-diethylaminoethanol.Fo1lowing theprocedure set forth in Example 1, part B, but substituting6-hydroxy-7-oxo-2-(3- trifiuoromethylstyryl) 1,3,5 cycloheptatriene 1carboxylic acid for6-hydroxy-7-oxo-2-styryl-l,3,5-cycloheptatriene-l-carboxylic acid, thereis obtained 6-hydroxy-7- oxo-2-(3-trifluoromethylstyryl) 1,3,5cycloheptatrienel-carboxylic acid, ester with Z-diethylamino ethanol.

Similarly, following the procedures of Examples 4 and 5 but employing6-hydroxy-7-oxo-2-(3-trifluoromethylstyryl)-1,3,5-cycloheptatriene-l-carboxylicacid yields the dimethylaminopropanol ester and theN'-(3-hydroxypropyl)-N -methylpiperazine ester thereof respectively.

EXAMPLE 8 6-hydroxy 7 oxo 2 (3,4,5 trimethoxystyryl) 1,3,5-cycloheptatriene-l-carboxylic acid, ester with Z-diethylaminoethanol A.6-hydroxy-7-oxo-2-(3,4,5 trimethoxystyryl 1,3,5-cycloheptatriene-l-carboxylic acid.Following the procedure set forth inExample 1, part A, but substituting an equivalent amount of3,4,5-trimethoxybenzaldehyde for benzalde-hyde there is obtained6-hydroxy-7-oxo-2-(3,4,5- trimethoxystyryl) 1,3,5cycloheptatriene-l-carboxylic acid.

B. 6-hydroxy 7 oxo 2 (3,4,5-trimethoxystyryl)-1,3,5-cycloheptatriene-l-carboxylic acid, ester with2-diethylaminoethanol.-Following the procedure set forth in Example 1,part B, but substituting 6-hydroxy-7-oxo-2- (3,4,5-trimethoxystyryl)1,3,5 cycloheptatriene-l-carboxylic acid for6-hydroxy-7-oxo-2-styryl-1,3,5-cycloheptatriene-l-carboxylic acid thereis obtained 6-hydr0xy-7- oxo-2-(3,4,5-trimethoxystyryl) 1,3,5cycloheptatrienel-carboxylic acid, ester with Z-diethylaminoethanol.

Similarly, following the procedures set forth in Examples 4 and 5 'butemploying 6-hydroxy-7-oxo-2-(3,4,5-trimethoxystyryl)-l,3,5-cycloheptatriene l carboxylic acid yields theZ-dimethylaminopropanol and N-(3-hydroxypropyl)-N -methy1piperazineesters thereof, respectively.

. EXAMPLE 9 G-hydroxy 7 oxo 2(indolyl-fi-vinylene)-1,3,5-cycloheptatriene 1 carboxylic acid, esterwith 2-diethylaminoethanol A. 6-hydroxy 7 oxo 2(indolyl-B-vinylene)-1,3,5- cycloheptatriene-l-carboxylic acid.Following the procedure set forth in Example 1, part A, but substitutingan equivalent amount of fi-indolealdehyde for benzaldehyde there isobtained 6-hydroxy-7-oxo-2-(indolyl-B-vinylene)-1,3,5-cycloheptatrienel-carboxylic acid.

B. 6-hydroxy 7 oxo 2 (indolyl-B-vinylene)-1,3,5-cycloheptatriene-l-carboxylic acid, ester withZ-diethylaminetl1anol.Following the procedure set forth in Example 1,part B, but substituting 6-hydroxy-7-oxo-2-(indolyl-fl-vinylene) 1,3,5cycloheptatriene 1 carboxylic acid for6-hydroxy-7-oxo-2-styryl-1,3,5-cycloheptatrienel-carboxylic acid thereis obtained 6-hydroxy-7-oxo-2-(indolyl-[i-vinylene)-1,3,5-cyclol1eptatriene l carboxylic acid, esterwith 2-diethylaminoethanol.

Similarly, following the procedure set forth in EX amples 4 and 5 butemploying 6 hydroxy-7-oxo-2-(indolylfl-vinylene)-l,3,5-cycloheptatriene1 carboxylic acid yields the Z-dimethylaminopropanol andN-(3-hydroxypropyl)-N -methylpiperazine esters thereof respectively.

EXAMPLE 10 6-hydroxy 7 oxo 2 (furyl-a-vinylene)-1,3,5-cycloheptatriene lcarboxylic acid, ester with Z-diethylaminoethanol A. 6-hydroxy 7 oxo 2(furyl-u-vinylene)-1,3,5- cycloheptatriene-l-carboxylic acid.-Followingthe procedure set forth in Example 1, part A, but substitutingafuraldehyde for benzaldehyde there is obtained 6-hydroxy- 7-oxo-2(furyl-vt-vinylene)-1,3,5-cycloheptatriene-l-carboxylic acid.

Similarly, following the procedure of Example 1, part A, butsubstituting S-nitro-a-furaldehyde for benzaldehyde there is obtained6-hydroxy-7-oxo-2(5-nitrofuryl-ot-vinylene)-1,3,5-cycloheptatriene-l-carboxylic acid.

B. 6-hydroxy 7 oxo 2 (furyl-u-vinylene)4,3,5-cycloheptatriene-l-carboxylic acid, ester with2-diethylaminoethanol.-Following the procedure set forth in Example 1,part B, but substituting 6-hydroxy-7-oxo-2- (furyl-a-vinylene) 1,3,5cycloheptatriene-l-carboxylic acid for6-hydroxy-7-0xo-2-styryl-1,3,5-cycloheptatrienel-carboxylic acid thereis obtained 6-hydroxy-7-oxo-2- (furyl-a-vinylene)-1,3,5-cycl0heptatriene1 carboxylic acid, ester with Z-diethylaminoethanol.

Similarly, following the procedure set forth in Example 1 part B, butsubstituting 6-hydroxy-7-oxo-2-(S-nitrofuryl-a-vinylene) 1,3,5cycloheptatriene 1 carboxylic acid for6-hydroxy-7-oxo2-styryl-1,3,5-cycloheptatrienel-carboxylic acid there isobtained 6-hydroxy-7-oxo-2(5- nitrofuryl-a-vinylene)-1,3,5-cycloheptatriene 1 carboxylic acid, ester withZ-diethylaminoethanol.

Similarly, following the procedure set forth in Examples 4 and 5 butemploying 6-hydroxy-7-oxo-2-(furyla vinylene) 1,3,5cycloheptatriene'l-carboxylic acid yields the 2-dimethylarninopropanoland N-(3-hydroxypropyl)-N -methylpiperazine esters thereof respectively.

EXAMPLE 11 6 hydr-oxy 7oxo-2-(naphthyl-ot-vinylene)-1,3,5-cycloheptatriene -1-carboxylic acid,ester with Z-diethylaminoethanol A. 6-hydroxy-7-oxo-2-(naphthyl ccvinylene)-1,3,5- cycloheptatriene-l-carboxylic acid.Following theprocedure of Example 1, part A, but substituting a-naphthaldehyde forbenzaldehyde there is obtained 6-hydroxy-7- oxo-2-(naphthyl-a-vinylene)1,3,5 cycloheptatriene-lcarboxylic acid.

B. -6-hydroxy 7 oxo-2-(naphthyl-a-vinylene)-1,3,5-cycloheptatriene-l-carboxylic acid, ester withZ-diethylalminoethanol.Following the procedure of Example 1, part B, butsubstituting6-thydroxy-7-oxo-2-(naphthyl-avinylene)-1,3,5-cycloheptatriene-l-carboxylicacid for 6- hydroxy-7-oxo-2-styryl 1,3,5 cycloheptatriene-l-carboxylicacid there is obtained6-hydroxy-7-oxo-2-(naphthyl-a-vinylene)-1,3,5-cycloheptatriene 1carboxylic acid, ester with 2-diethylaminoethanol.

Similarly, following the procedure set forth in Examples 4 and 5 butemploying 6-hydroxy-7-oxo-2-(naphthyl-a-vinylene)41,3,5-cyc1oheptatriene1 carboxylic acid yields the Z-dimetahylaminopropanol andN-(3-hydroxypropyl)-N -methylpiperazine esters thereof respe tively.

EXAMPLE 12 6-hydroxy 7 oxo-2-(pyridyl-y-vinylene)-1,3,5-cycl0-heptatriene-l carboxylic acid, esther with Z-diethvlaminoethanol A.fi-hydroxy 7 oxo-2-(pyridyl-y-vinylene)-1,3,5- cycloheptatriene 1carboxylic acid.-Following the procedure set forth in Example 1, part A,but substituting pyridine-'y-aldehyde for benezaldehyde there isobtained 6-hydroxy 7 oxo2-(pyridyl-'-vinylene)1,3,5-cyclohept-atriene-l-carboxylic acid.

B. =6-hydr0xy 7 oxo-2-(pyridyl-y-vinylene)-1,3,5-cycloheptatriene-l-carboxylic acid, ester withZ-diethylaminoethanol.-Following the procedure set forth in Example 1,part B, but substituting 6-hydroxy-7-oxo-2-(pyridyl-y-vinylene)-l,3,5-cycloheptatriene 1 carboxylic acid for6-hydroxy 7 oxo-2-styryl-1,3,5-cycloheptatriene-l-carboxylic acid thereis obtained 6-hydroxy-7- oxo-2-(pyridyl-y-vinylene) 1,3,5cycloheptatriene-lcarboxylic acid, ester with 2-diethylaminoethanol.

Similarly, following the procedure set forth in Example 4 and 5 butemploying 6-hydroxy-7-oxo-2-(pyridyl-'y-vinylene)-1,3,5-cycloheptatriene 1 carboxylic acid yields theS-dimethylarnino propane! and N-(3-hydroxypropyl)-N methylpiperazineesters thereof respectively.

EXAMPLE 13 6-hydroxy 7 oxo-2-(thienyl-a-vinylene)-1,3,5-cycloheptatriene1 carboxylic acid, ester with Z-diethylaminoethanol A. 64hydr0xy 7oxo-2-(thienyl-ot-vinylene)-1,3,5-

cycloheptatriene-l-carboxylic acid.-Following the procedure set forth inExample 1, part A, but substituting Z-thiophenealdehyde for benzaldehydethere is obtained 6-hydroxy 7 oxo-2-(thienyl-a-vinylene)-1,3,5-cycloheptatriene-l-carboxylic acid.

B. '6-hydroxy 7 oxo-2-(thienyl-u-vinylene)-1,3,5-cycloheptatriene-l-carboxylic acid, ester withZ-diethylaminoethanol.-Following the procedure set forth in Example 1,part B, but substituting 6-hydroxy-7-oxo-2-(thienyl-a-vinylene)-1,3,5-cycloheptatriene 1 carboxylic acid there isobtained6-hydroxy-7-oxo-2-(thienyla-vinylene)-l,3,5-cycloheptatriene-l-carboxylicacid, ester with Z-diethylaminoethanol.

Similarly, following the procedure set forth in Examples 4 and butemploying6-hydroxy-7-oxo-2-(thienyla-vinylene)-l,3,5-cycloheptatriene1-carboxylicacid yields the Z-dimethylaminopropanol and N-(3-hydroxypropyl)- N-methylpiperazine esters thereof respectively.

EXAMPLE 14 6-hydroxy 7oxo-2-(p-nitrostyryl)-1,3,5-cycloheptatriene-l-carboxylic acid, esterwith 2-diethylaminoethanol A. 6-hydroxy 7oxo-Z-(p-nitrostyryl)-1,3,5-cycloheptatriene-l-carboxylic acid.Followingthe procedure set forth in Example 1, part A, but substitutingp-nitrobenzaldehyde for benzaldehyde there is obtained 6-hydroxy 7oxo-Z-(p-nitrostyryl)-l,3,5-cycloheptatrienel-carboxylic acid.

B. 6-hydroxy 7 oxo-2-(p-nitrostyryl)-l,3,5-cycloheptatriene-l-carboxylicacid, ester with Z-diethylaminoethanoL-Following the procedure set forthin Example 1, part B, but substituting6-hydroxy-7-oxo-2-(p-nitrostyryl)-1,3,5-cycloheptatriene l carboxylicacid for 6- hydroxy-7-oxo 2 styryl-1,3,5-cycloheptatriene-l-carboxylicacid there is obtained6-hydroxy-7-oxo-2-(p-nitrostyryl)-1,3,5-cycloheptatriene 1 carboxylicacid, ester with 2-diethylaminoethanol.

Similarly, following the procedure set forth in Examples 4 and 5 butemploying 6-hydroxy-7-oxo-2-(pnitrostyryl)-l,3,5-cycloheptatriene 1carboxylic acid yields the Z-dimethylaminopropanol andN-(3-hydroxypropyl)-N -methylpiperazine esters thereof respectively.

EXAMPLE l5 6-hydroxy 7 oxo-Z-(4-methylstyryl)-1,3,5-cycloheptatriene 1carboxylic acid, ester with Z-diethylaminoethanol A. 6-hydroxy 7oxo-2-(4'-methylstyryl)-1,3,5-cycloheptatriene-l-carboxylic-acid.Following the procedure set forth in Example 1, part A, butsubstituting p-to-lylaldehyde for benzaldehyde there is obtained6-hydroxy-7- oxo-2-(4-methylstyryl) 1,3,5 cycloheptatriene 1 carboxylicacid.

B. 6-hydroxy 7oxo-2-(4-methylstyryl)-1,3,5-cycloheptatriene-l-carboxylic acid, esterwith Z-diethylaminoethanol.-Following the procedure set forth in Example1, part B, but substituting6-hydroxy7-oxo-2-(4-methylstyryl)-l,3,5-cycloheptatriene-1-carboxylicacid for 6-hydroxy-7-oxo-2-styryl 1,3,5 cycloheptatriene-l-carboxlieacid there is obtained6-hydroxy-7-oxo-2-(4-methylstyryl)-1,3,5-cycloheptatriene 1 carboxylicacid, ester with Z-diethylaminoethanol.

Similarly, following the procedure set forth in Examples 4 and 5 butemploying 6-hydroxy-7-oxo-2-(4- methylstyryl)-1,3,5-cycloheptatriene lcarboxylic acid yields the Z-dimethylarninopropanol and N-methylpiperazine esters thereof respectively.

EXAMPLE 16 6-hydroxy 7 oxo-Z-styryl-1,3,5-cycloheptatriene-1-carboxylicacid, ester with methylaminomethanol Following the procedure of Example1, part B, but

substituting an equivalent amount of methylaminoethyl chloride forZ-diethylaminoethyl chloride yields 6 hydroxy-7-oxo-2-styryl 1,3,5cycloheptatriene-l-carboxylic acid, ester with methylaminomethanol.

EXAMPLE 17 6-hydroxy-7-oxo-2-styryl 1,3,5- cycloheptatriene-carboxylicacid, ester with 2-benzylaminoethanol Following the procedure of Example1, part B, substituting an equivalent amount of Z-benzylaminoethylchloride for 2-diethylaminoethyl chloride yields6-hydroxy-7-oxo-2-styryl 1,3,5 cycloheptatriene-l-carboxylic acid, esterwith Z-benzylaminoethanol.

EXAMPLE 18 6-hydroxy-7-oxo-2-styryl-1,3,5-cyclol1eptatriene-l-carboxylicacid, ester with 3-diallylaminopropanol Following the procedure ofExample 1, part B, but substituting an equivalent amount of3-diallylaminopropyl chloride for Z-diethylaminoethyl chloride yields6hydroxy 7 oxo 2 styryl 1,3,5 cycloheptatriene 1 carboxylic acid, esterwith 3-diallylaminopropanol.

EXAMPLE 19 6-hydroxy-7-oxo-2-styryl-1,3,5-cycloheptatriene-l-carboxylicacid, ester with 2-(2-hydroxyethyl)aminoethanol Following the procedureof Example 1, part B, but substituting an equivalent amount of2-(2-hydroxyethyl) aminoethyl chloride for 2-diethylaminoethyl chlorideyields 6-hydroxy-7-oxo-2-styryl-1,3,5-cycloheptatriene-lcarboxylic acid,ester with 2-(2-hydroxyethyl)aminoethanol.

This invention may be variously otherwise embodied within the scope ofthe appended claims.

What is claimed is:

1. A compound selected from the group consisting of bases of the formulalions. l

and pharmaceutically acceptable non-toxic acid-addition and quaternaryammonium salts thereof, wherein A is lower alkylene; B is a basicnitrogen containing radical of less than twelve carbon atoms selectedfrom the group consisting of amino, (lower alkyl)amino; di(lower alkyl)amino; (hydroxy-lower alkyl)amino; di(hydroxy-lower alkyl)amino;(X),,-substituted phenyl(lower alkyl) amino; N (lower alkyl) N [(X)substituted phenyl(lower alkyl) ]-amino; allylamino; diallylamino;piperidino; piperidyl; (N-lower alkylpiperidyl); pyrrolidino;pyrrolidyl; (N-lower alkylpyrrolidyl); morpholino; thiamorpholino;piperazino; (lower alkyl)piperazino; di(lower alkyl)piperazino; (loweralkoxy)piperazino; (hydroxylower alkyl)piperazino; (loweralkanoyloxy-lower alkyl) piperazino; and (hydroxy-lower alkoxy-loweralkyl) piperazino and R is thienyl, furyl, nitrofuryl, pyridyl, naphthylor indole; and n is a positive integer less than four.

2. A compound in accordance with claim 1 having the name6-hydroxy-7-oxo-2-(furyl-a-vinylene)-l,3,5-cycloheptatriene-l-carboxylic acid, ester with Z-diethylaminoethanol,and pharmaceutically acceptable non-toxic acid-addition and quaternaryammonium salts thereof.

3. A compound in accordance with claim 1 having the name6-hydroxy-7-oxo-2-(5-nitrofuryl-u-vinylene)-l,3,5-cycloheptatriene-l-carboxylic acid, and pharmaceuticallyacceptable non-toxic acid-addition and quaternary ammonium saltsthereof.

4. A compound in accordance with claim 1 having the name6-hydroxy-7-oxo-2-(thienyl-a-vinylene)-1,3,5-

9 10 cycloheptatriene-l-carboxylic acid, ester with 2-diethyl-References Cited aminoethanol and pharmaceutically acceptable non-toxicUNITED STATES PATENTS acid-addition and quaternary ammonium saltsthereof.

5. A compound in accordance with claim 1 having the name6-hydroxy-7-oxo-2-(pyridyl-y-vinylene)-1,3,5cycloheptatriene-l-carboxylic acid, ester with Z-diethyl- 5 JOHNRANDOLPH Pr'mary Exammer' aminoethanol and pharmaceutically acceptablenon-toxic U S Q X R acid-addition and quaternary ammonium salts thereof.

3,326,963 6/1967 Krapcho 260473

